tbuckley/cabot-search huggingface dataset:
Abstract 5804: Targeting methyl donor synthesis inhibits platinum-induced enrichment of ovarian cancer stem cells
Authors: Shu Zhang, Tara X. Metcalfe, Christiane A. Hassel, Heather M. O'Hagan, Kenneth P. Nephew
Journal: Cancer Research (2023)

Abstract Ovarian cancer (OC) is one of the deadliest gynecologic cancers in US. Platinum (Pt)-based chemotherapy can reprogram cancer cells to ovarian cancer stem cells (OCSCs) and contribute to incurable recurrence. We have previously shown that Pt-containing drugs, e.g., cisplatin, enrich for OCSCs and Pt-induced alterations in DNA methylation enhanced OCSC malignant properties. CSCs have been shown to be dependent on methionine (Met) in many cancers, and in the current study, we investigated the role of Met and the interplay between methylation and Met metabolism in OCSC enrichment. In high grade serous ovarian cancer cell lines (OVCAR5, OVCAR3), cisplatin treatment (IC50, 16hr) increased (p&amp;lt;0.01) the percentage of cells that were positive for aldehyde dehydrogenase (ALDH+ cells), a known OCSCs marker. Cisplatin treatment also increased (p&amp;lt;0.05) the whole cell level of 5-methylcytosine, indicating Pt-induced methylation changes. In addition, Met metabolism was altered by cisplatin, demonstrated by decreased (p&amp;lt;0.01) level of Met derivative, S-adenosyl-methionine (SAM), and increased (p&amp;lt;0.01) expression of Met utilization enzyme, methionine adenosyltransferase 2A (MAT2A). To investigate a possible role of Met metabolism in Pt-induced enrichment of OCSCs, OVCAR5 cells were cultured in complete or Met-depleted (Met-) media, treated with cisplatin or vehicle and examined for CSC properties, including ALDH+ cells and the ability to form spheroids under low-attachment conditions. Met depletion blocked (p&amp;lt;0.01) both the Pt-induced increase of ALDH+ cells and spheroid formation. Both Met- only and Met- in combination with cisplatin activated p38, determined by increased phosphorylated p38, which may have responded to Met depletion and promoted cell cycle arrest. In addition, MAT2A expression was higher (p&amp;lt;0.01) in ALDH+ compared to ALDH- OC cells. MAT2A inhibitor FIDAS-5 combined with cisplatin blocked the Pt-induced increase in ALDH+ cells (p&amp;lt;0.01), demonstrating a requirement for Met utilization in Pt-induced OCSC enrichment. As MAT2A is a therapeutic target in cancer, MAT2A inhibition could represent a therapeutic approach for inhibiting CSC in ovarian cancer. We are further investigating the mechanism of MAT2A-mediated inhibition on Pt-induced OCSCs enrichment by examining the OC methylome and cell cycle arrest. Citation Format: Shu Zhang, Tara X. Metcalfe, Christiane A. Hassel, Heather M. O'Hagan, Kenneth P. Nephew. Targeting methyl donor synthesis inhibits platinum-induced enrichment of ovarian cancer stem cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5804.
Abstract 5818: Cadherin complexes recruit PIWIL2 to suppress pro-tumorigenic transformation
Authors: Alyssa Risner, Joyce Nair-Menon, Vamsi Gangaraju, Antonis Kourtidis
Journal: Cancer Research (2023)

Abstract Recent studies have shown that genomic instability, oncogene expression, and high mutation rates in more than 50% of tumors can be attributed to increased transposon activity. Transposons, also called transposable elements (TEs), are parasitic mobile DNA elements that make up 45% of the human genome and can cause DNA damage and gene mutations. The reasons for increased TE activity in somatic tumors are currently unknown. TE RNA transcripts are targeted for degradation by PIWI ribonucleases, which are members of the Argonaute superfamily of proteins, through regulation of small RNAs called piRNAs (PIWI-interacting RNAs). Although the function of the PIWI-piRNA pathway has been extensively studied in the germline, there is little understanding about the presence or functionality of the pathway in somatic tissues. We have evidence of a novel interaction of the adherens junctions of well-differentiated epithelial cells with PIWIL2 (PIWI-like RNA-Mediated Gene Silencing 2), a key catalytic component of the PIWI-piRNA complex. Through immunofluorescence staining, confocal microscopy, and co-immunoprecipitation studies, we found co-localization and association of PIWIL2, as well as of other key members of the PIWI complex, such as PIWIL4 and TDRD1, with E-cadherin and p120 catenin at adherens junctions of well-differentiated breast and colon epithelial cells, whereas this association is lost in cancer cells and patient tissues. Adherens junction disruption results in mis-localization of PIWIL2, PIWIL4, and TDRD1 from the adherens junctions and their accumulation either to the cytoplasm or to the nucleus. E-cadherin depletion particularly results in increased expression of the LINE1 transposon, which is the most abundant transposon in human cells, and in increased levels of γ-H2AX, an indicator of DNA damage. Our working hypothesis is that cadherin junctions of well-differentiated epithelial cells recruit and regulate the PIWIL2 complex to suppress transposon activity. Since both loss of junctional integrity and increased transposon activity are universal events in cancer, this study has the potential to deepen our understanding of the role of the PIWI-transposon pathway in somatic tumorigenesis. Citation Format: Alyssa Risner, Joyce Nair-Menon, Vamsi Gangaraju, Antonis Kourtidis. Cadherin complexes recruit PIWIL2 to suppress pro-tumorigenic transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5818.
Abstract 580: A novel drug suppresses pancreatic cancer growth through immunomodulation
Authors: Shreyas Ramchandra Gaikwad, Sanjay K. Srivastava
Journal: Cancer Research (2023)

Abstract Drug repurposing is an effective strategy that is being used to explore new potential treatments for various diseases. In the current study, utilizing drug repurposing approach, we have identified anti-cancer activity of an anti-parasitic compound (MB). We evaluated the anti-cancer activity of MB in pancreatic ductal adenocarcinoma (PDAC). The average IC50 of MB in several human and murine PDAC cells was 4-6µM. The mode of cell death was apoptosis and which was confirmed using Annexin-V assay. Oral administration of MB suppressed tumor growth in both human and murine subcutaneous and orthotopic models at a dose of 5mg/kg. In the syngeneic orthotopic model, MB showed immune modulation wherein it increased infiltration of CD8 T-cells in the tumor microenvironment as compared to control groups. Based on this, we combined MB with anti-PD1 therapy to evaluate the combinatorial effect. Our results showed significant PDAC tumor growth suppression when a combination of MB and anti-PD1 therapy was used in an orthotopic PDAC tumor model. In conclusion, MB has a promising anti-cancer effect against PDAC tumors and we are currently exploring the molecular mechanism of action in PDAC cell lines and also evaluating if MB has any direct effect on immune cell populations. Citation Format: Shreyas Ramchandra Gaikwad, Sanjay K. Srivastava. A novel drug suppresses pancreatic cancer growth through immunomodulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 580.
Abstract 5816: Tensin1 tension sensor reveals novel features associated with actomyosin, focal adhesion dynamics, and mechanosensitivity
Authors: Yoon-Kwan Jang, Jung-Soo Suh, Gyuho Choi, Sanghyun Ahn, Ki Seok Han, EunHye Kim, Yerim Lee, Xiaoqi Hu, Eunbae Hwang, Tae-Jin Kim
Journal: Cancer Research (2023)

Abstract Cellular responses to mechanical stimuli play an imperative role in the regulation of physiological and pathological functions. Unlike other integrin-mediated adhesion proteins, the force transmission mechanism of tensin1 is not well understood. In this study, we describe the development and visualization of a tensin1 tension sensor. A signal from this sensor indicates that tensin1 is under greater tension at peripheral adhesions than at central adhesions, and that it is controlled by actomyosin in fibroblasts. In a bidirectional manner, tension in tensin1 is regulated by focal adhesion kinase (FAK) activity. Our findings demonstrate that tensin1 is capable of sensing the extracellular matrix through alterations in the tension it receives from the extracellular matrix. Furthermore, tensin1 depletion increases the tension of talin1, but the absence of talin1 decreases the tension applied to tensin1. These results indicate that tensin1 is complementary and dependent on the tension received by talin1. Overall, our data, together with the prognosis following tensin1 expression in colorectal and urothelial cancer, elucidate the tension-receiving function of tensin1 and highlight the necessity of tensin1-mediated mechanotransduction studies. Citation Format: Yoon-Kwan Jang, Jung-Soo Suh, Gyuho Choi, Sanghyun Ahn, Ki Seok Han, EunHye Kim, Yerim Lee, Xiaoqi Hu, Eunbae Hwang, Tae-Jin Kim. Tensin1 tension sensor reveals novel features associated with actomyosin, focal adhesion dynamics, and mechanosensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5816.
Abstract 4955: Kurarinone, a natural notch signaling inhibitor and modulator of breast cancer stemness
Authors: Prem Prakash Kushwaha, Mohd Shuaib, Kumari Sunita Prajapati, Atul Kumar Singh, Mahesh Kulharia, Shashank Kumar, Sanjay Gupta
Journal: Cancer Research (2023)

Abstract Aberrant activation of Notch signaling pathway plays an important role in breast cancer development, progression, and stem cell renewal. Activation of Notch signaling is triggered by the interaction of Notch receptors with different ligands expressed on neighboring cells that bind and induce a second cleavage by a membrane-tethered metalloprotease. The remaining membrane-bound fragment is cleaved by γ-secretase (GS) releasing the Notch Intracellular Domain (NICD), which translocate to the nucleus to activate the expression of Notch target genes. Current indirect approaches to inhibit Notch signaling are based on agents that bind to GS substrates. In the search of novel Notch signaling inhibitor(s), we screened a number of plant flavonoids for their binding potential to GS substrate. Our in-silico study identified kurarinone (KU), a lavandulyl flavanone, having ability to bind to GS complex. The KU-GS complex was structurally and energetically stable during the molecular dynamics simulation period. Interestingly, dose and time dependent toxicity of KU was observed in T47D and MDA-MB-231 breast cancer cells at 1-25µM concentration. KU treatment of cells led to inhibition in cyclin D1 expression, arrest of cells in the G1 phase of the cell cycle and subsequently undergoes apoptosis. KU-mediated apoptosis was a result of altered mitochondria membrane potential and increased ROS production. In dual-luciferase Notch promoter assay, KU inhibited GS-mediated NICD production in transfected HEK293 cells. Furthermore, KU treatment decreased the mammosphere formation potential of MCF-7 cells through altered gene expression involved in self-renewal and stemness. KU treated MDA-MB-231 cells and MCF-7 derived mammosphere showed downregulation of Notch signaling through alteration in the expression of downstream genes such as Hey1, Hes1, and E-cadherin at both transcript and protein levels. Taken together, the present study identified KU as a novel natural Notch signaling inhibitor that could provide a novel and safer approach for the treatment of breast cancer through reduction in stemness and self-renewal properties. Citation Format: Prem Prakash Kushwaha, Mohd Shuaib, Kumari Sunita Prajapati, Atul Kumar Singh, Mahesh Kulharia, Shashank Kumar, Sanjay Gupta. Kurarinone, a natural notch signaling inhibitor and modulator of breast cancer stemness. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4955.
Abstract 2448: Galectin-3 regulates stemness and cellular states in glioblastoma stem cells
Authors: Bedia Akosman, Shaan Lalvani, Yusuke Suita, David Karambizi, Nikos Tapinos
Journal: Cancer Research (2023)

Abstract Glioblastoma stem cells (GSCs) are a subset of cells in the Glioblastoma (GBM) tumor microenvironment that play an important role in tumor heterogeneity, aggressiveness, recurrence, and therapy resistance. Dynamic environmental, transcriptional, and epigenetic oscillations envelope GSCs in a variety of cellular states, contributing to GSC heterogeneity and carcinogenesis. The creation of effective therapies may therefore benefit from a better understanding of the factors associated with the GSC's distinct traits as well as the mechanisms affecting GSC cellular states and transformation. Galectin-3 is a molecule that is highly expressed in GBM, and higher levels are linked to poor survival and mesenchymal subtype. Although Galectin-3 has previously been found primarily in microglia and tumor-infiltrating macrophages, our studies using patient-derived GSCs show that it is abundantly produced by GSCs and that its expression significantly decreases when they differentiate into non-stem differentiated cancer cells, which are more responsive to therapies. Our findings also show that Galectin-3 is not expressed in normal neural stem cells, leading us to believe that it could serve as a unique identifier for GSCs. Additionally, when Galectin-3 is silenced in GSCs, we see a decreased self-renewal frequency and enrichment of genes associated with pro-neural state, which has a less aggressive phenotype. Confocal imaging and single-cell RNA-seq analysis further revealed heterogeneous expression of Galectin-3 in GSCs, and the functional pathway analysis shows that Galectin-3high cell clusters have a significant overlap with cells enriched in EMT pathways. Therefore, our findings suggest that Galectin-3 may be a unique distinguishing characteristic of GSCs and may play a particular role in regulating GSC stemness and determining GSCs states, making it a potential molecular target for the treatment of glioblastoma. Citation Format: Bedia Akosman, Shaan Lalvani, Yusuke Suita, David Karambizi, Nikos Tapinos. Galectin-3 regulates stemness and cellular states in glioblastoma stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2448.
Abstract 4968: Characterization of the clinical development candidate TNG348 as a potent and selective inhibitor of USP1 for the treatment of BRCA1/2mut cancers
Authors: Antoine Simoneau, Hsin-Jung Wu, Madhavi Bandi, Katherine Lazarides, Sining Sun, Shangtao Liu, Samuel Meier, Ashley Choi, Hongxiang Zhang, Binzhang Shen, Douglas Whittington, Sirimas Sudsakorn, Wenhai Zhang, Yi Yu, Yong Liu, Colin Liang, Michael Palmieri, Yingnan Chen, Brian Haines, Alice Tsai, Minjie Zhang, Alan Huang, Jannik Andersen, Tianshu Feng, Scott Throner, John Maxwell
Journal: Cancer Research (2023)

Abstract TNG348 is a selective and potent inhibitor of the deubiquitinating enzyme USP1 specifically designed to target BRCA1/2mut vulnerabilities in breast and ovarian tumors. Here we present the biochemical, mechanistic, and in vitro and in vivo characterization of TNG348, an oral, allosteric and highly potent inhibitor of USP1. Upon treatment, TNG348 causes loss of viability in a panel of breast and ovarian BRCA1/2mut cancer cell lines and displays dose-dependent tumor growth inhibition in BRCA1/2mut xenograft models. Furthermore, TNG348 activity extends beyond BRCA1/2mut models with PARP inhibitor (PARPi) sensitivity and oncogene-induced replication stress being additional features correlating with USP1 inhibitor sensitivity based on cell line panel and CRISPR screening results. We show that TNG348 induces cell death through a pathway that is distinct from PARPi and TNG348 demonstrates robust synergy when combined with first- or second-generation PARPi. The clinical development plan intends to evaluate TNG348 in patients with BRCA1/2 mutations as single agent and in combination with PARP1i in patients naïve to PARPi and with prior PARPi treatment history. Citation Format: Antoine Simoneau, Hsin-Jung Wu, Madhavi Bandi, Katherine Lazarides, Sining Sun, Shangtao Liu, Samuel Meier, Ashley Choi, Hongxiang Zhang, Binzhang Shen, Douglas Whittington, Sirimas Sudsakorn, Wenhai Zhang, Yi Yu, Yong Liu, Colin Liang, Michael Palmieri, Yingnan Chen, Brian Haines, Alice Tsai, Minjie Zhang, Alan Huang, Jannik Andersen, Tianshu Feng, Scott Throner, John Maxwell. Characterization of the clinical development candidate TNG348 as a potent and selective inhibitor of USP1 for the treatment of BRCA1/2mut cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4968.
Abstract 5805: Ebastine targets cancer stem cell-like properties and metastasis in triple-negative breast cancer by binding focal adhesion kinase
Authors: Juyeon Seo, Minsu Park, Dongmi Ko, Seongjae Kim, Soeun Park, Kee Dal Nam, Yong Koo Kang, So Ra Seuk, Jaeyoun Park, Eunsun Jung, Yoon-Jae Kim, Ji Young Kim, Jae Hong Seo
Journal: Cancer Research (2023)

Abstract Triple-negative breast cancer (TNBC) exhibits an aggressive behavior associated with poor prognosis due to the absence of established molecular targets. Focal adhesion kinase (FAK) is a major determinant and participates in the acquisition of migration and invasion, as well as the maintenance of breast cancer stem cell (BCSC)-like traits in TNBC. We sought to investigate the effect of ebastine, a second-generation antihistamine on apoptosis, FAK activation, BCSC subpopulations and metastasis in TNBC in vitro and in vivo. TCGA dataset analysis revealed that mRNA levels of FAK were highly expressed in TNBC compared to other breast cancer subtypes. We found that ebastine binds to the tyrosine kinase domain of FAK, which blocks phosphorylation at the Y397 and Y576/577 residues and subsequent inactivation of SRC. Ebastine-induced apoptosis was associated with attenuation of JAK2/STAT3 and MEK/ERK signaling in TNBC cells. Kinetic analysis revealed a concentration-dependent impairment of cell migration in the presence of ebastine in MDA-MB-231 and 4T1 cells in vitro. Ebastine targets BCSC-like cell populations as evidenced by a sharp decline in the expression of the BCSC markers ALDH1, CD44 and CD49f and suppression of mammosphere-forming capacity. Ebastine administration led to a significant reduction in the growth ebastine of BCSC-enriched 4T1 mammospheres orthotopically injected into the mammary glands of Balb/c mice. Ebastine administration significantly impeded angiogenesis and distant metastasis while reducing MMP-2/-9 levels in circulating blood in vivo. Importantly, biochemical analysis in mice serum showed that ebastine had no effect on liver and kidney function. Our findings suggest that EBA may be an effective therapeutic repositioning candidate for the simultaneous targeting of multiple survival signaling pathways for the treatment of molecularly heterogeneous TNBC. Further investigation of ebastine as an anti-metastatic agent for the treatment of TNBC is warranted. Citation Format: Juyeon Seo, Minsu Park, Dongmi Ko, Seongjae Kim, Soeun Park, Kee Dal Nam, Yong Koo Kang, So Ra Seuk, Jaeyoun Park, Eunsun Jung, Yoon-Jae Kim, Ji Young Kim, Jae Hong Seo. Ebastine targets cancer stem cell-like properties and metastasis in triple-negative breast cancer by binding focal adhesion kinase. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5805.
Abstract 5806: Kinase library screening identifies IGF-1R/PI3K/AKT axis as a crucial pathway for survival of intrahepatic cholangiocarcinoma cells with stemness characteristics
Authors: Chotirat Rattanasinchai, Chidchanok Chornkrathok, Donlaporn Sriphan, Panida Navasumrit, Mathuros Ruchirawat
Journal: Cancer Research (2023)

Abstract Intrahepatic cholangiocarcinoma (iCCA) is a subtype of biliary malignancy that arises along the peripheral bile duct epithelium. Given its limited and inefficacious treatment options, the mortality rate of iCCA remains high and thus a novel therapeutic strategy is urgently needed. The concept of cancer stem cells (CSCs) explains a subpopulation of cancer cells that possesses self-renewal and differentiation capacities. These CSCs become the culprit for cancer metastasis, cancer recurrence and chemotherapeutic resistance, making them promising targets for cancer treatment. The propose of this study is to identify the signaling pathways crucial for the survival of iCCA with stemness characteristics. Gene expression analysis on a dataset of Thai iCCA patients (n=91) showed that iCCA tumors are enriched in the Adult Stem Cell (ASC) signature which are the shared characteristics among the epithelial-derived cancer with stemness characteristics. Although iCCA cells exhibit some degree of enrichment in stem cells markers when compared with cholangiocyte cells, further upregulation of stem cell-related genes, e.g. Nanog, Oct3/4, Sox2, and Sox9, were found in iCCA cells grown as 3D tumorspheres. A kinase inhibitor screening library was then performed on iCCA tumorspheres. Our initial screening demonstrated that 11 out of the top 50 kinase inhibitors that effectively decrease viability of iCCA tumorspheres belongs to the insulin-like growth factor-1 receptor (IGF-1R)/phosphoinositide-3-kinase (PI3K)/protein kinase B (PKB/AKT) axis. Additionally, these inhibitors increase cell apoptosis, judged by the caspase 3/7 activity, within iCCA tumorspheres. Conversely, IGF-1 treatment which is sufficient to induce activation of IGF-1R and AKT also enhances cell viability and decrease cell apoptosis in iCCA. Taken together, our data demonstrate that IGF-1R/PI3K/AKT axis is crucial for survival of iCCA cells with stemness characteristics and this pathway could be a potential therapeutic target in iCCA. Citation Format: Chotirat Rattanasinchai, Chidchanok Chornkrathok, Donlaporn Sriphan, Panida Navasumrit, Mathuros Ruchirawat. Kinase library screening identifies IGF-1R/PI3K/AKT axis as a crucial pathway for survival of intrahepatic cholangiocarcinoma cells with stemness characteristics. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5806.